EP2451796B1 - Tofa-analoga zur behandlung von hauterkrankungen oder -störungen - Google Patents

Tofa-analoga zur behandlung von hauterkrankungen oder -störungen Download PDF

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Publication number
EP2451796B1
EP2451796B1 EP10732576.3A EP10732576A EP2451796B1 EP 2451796 B1 EP2451796 B1 EP 2451796B1 EP 10732576 A EP10732576 A EP 10732576A EP 2451796 B1 EP2451796 B1 EP 2451796B1
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Prior art keywords
optionally substituted
tetradecyloxy
furan
carboxylate
compound
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EP10732576.3A
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English (en)
French (fr)
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EP2451796A1 (de
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Timothy Scott Daynard
Geoffrey C. Winters
David W.C. Hunt
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Dermira Canada Inc
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Dermira Canada Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
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    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/58—One oxygen atom, e.g. butenolide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention is directed to analogs of 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA) for use in the treatment of dermatological disorders or conditions characterized by sebaceous gland hyperactivity, such as acne and oily skin.
  • TOFA 5-(tetradecyloxy)-2-furancarboxylic acid
  • This invention is also directed to pharmaceutical and dermatological compositions comprising analogs of TOFA for use in treating dermatological disorders or conditions characterized by sebaceous gland hyperactivity, such as acne and oily skin.
  • Hyperactive sebaceous gland disorders such as acne vulgaris (acne) are common dermatological conditions affecting many people. Acne typically presents at the onset of puberty and peaks in incidence between 14 and 19 years of age. The prevalence of acne is greatly reduced by the middle of the third decade of life. Acne pathogenesis is multi-factorial involving sebaceous gland hyperactivity (increased production of sebum) with seborrhea, abnormal keratinocyte proliferation/desquamation and bacterial colonization promoting local inflammatory changes. As a consequence of the surge in androgen production at puberty, increased sebum production occurs along with abnormal desquamation of the epithelial lining of hair follicles.
  • This mixture of sebum and cell debris is the basic ingredient of the comedone providing an ideal environment for the growth of Propionibacterium acnes ( P. acnes), an anaerobic gram-positive bacterium that is part of normal skin flora and a key contributor to inflammatory acne.
  • P. acnes Propionibacterium acnes
  • Bacterial-derived chemotactic factors and pro-inflammatory mediators subsequently foster local inflammatory reactions.
  • the clinical presentation of acne ranges from open comedones (whiteheads) and closed comedones (blackheads) for mild acne to the papules, pustules, nodules and cystic or mixed lesions for severe, inflammatory acne.
  • Acne lesions typically occur on the face, upper back, chest and upper arms.
  • the clinical course of acne tends to wax and wane.
  • the severity of the condition is affected by multiple factors including seasonal and psychological influences as well as self-induced trauma by patients who habitually manipulate their lesions.
  • moderate to severe inflammatory acne presents a true disease state that may cause long-term consequences for the subject including, but not limited to, socially disabling psychological damage and disfiguring physical scars.
  • a wide array of therapies for treating from moderate to severe acne is available. These therapies may affect specific aspects of the condition or in some cases affect several pathogenic factors.
  • Dermatological therapies are not fully effective against mild to moderate acne and many of the agents employed in these therapies produce skin irritation.
  • therapies employing dermatological retinoids and benzoyl peroxide are effective against mild to moderate acne by removing comedones, killing bacteria and/or reducing inflammation.
  • therapies employing antibiotics given either dermatologically or orally, may be used to treat mild to moderate acne through the antibiotics' bacteriostatic and anti-inflammatory activities. Oral antibiotics do not typically produce satisfactory lesion clearance.
  • antibiotics used in the treatment of acne are slow-acting and require a treatment period of 3-6 months for optimum results. Hence compliance may be difficult, especially among younger patients. Long-term use of antibiotics is also associated with the spectre of bacterial antibiotic-resistance.
  • Light-based therapies such as 420-nm blue light or 1450-nm thermal lasers, can be used to treat mild to moderate acne based on their respective anti-bacterial photodynamic or thermal effect on sebaceous glands.
  • first line therapy may consist of an oral retinoid, such as Accutane® (13-cis-retinoic acid).
  • Accutane® has a strong inhibitory action on sebaceous glands and is therefore useful in removing comedones, reducing inflammation and inhibiting proliferation, differentiation and lipogenesis within sebaceous glands.
  • Accutane® is also used to treat moderate or severe acne in patients at risk of physical or psychological scarring.
  • Accutane® has long history of proven efficacy in treating acne.
  • LTB4 leukotriene B4
  • Described herein are analogs of 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA) and methods for using the analogs for the treatment of dermatological disorders or conditions characterized by sebaceous gland hyperactivity, such as acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin.
  • TOFA 5-(tetradecyloxy)-2-furancarboxylic acid
  • this invention is directed to compounds of formula (I): wherein:
  • Another aspect of this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), as set forth above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, and said composition for use in
  • a method of treating a human having a dermatological disorder or condition characterized by sebaceous gland hyperactivity comprises administering to the human in need thereof a therapeutically effective amount of a compound of formula (I), as set forth above, or a pharmaceutically acceptable salt thereof.
  • this invention is directed to said pharmaceutical composition for use in a method of treating a human having a disorder or condition characterized by inflammation, wherein the method comprises administering to the human in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), as set forth above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), as set forth above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Another aspect of this invention is directed to said pharmaceutical composition for use in a method of reducing T cell proliferation and cytokine secretion in a human having a disorder or condition characterized by inflammation, the method comprising administering to the human in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), as set forth above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), as set forth above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • C 7 -C 12 alkyl describes an alkyl group, as defined below, having a total of 7 to 12 carbon atoms
  • C 4 -C 12 cycloalkylalkyl describes a cycloalkylalkyl group, as defined below, having a total of 4 to 12 carbon atoms.
  • the total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the group described.
  • a suitable dermatologically acceptable excipient may include one or more penetration enhancers (or permeation enhancers), which are substances that promote the diffusion of the therapeutic drugs (e.g ., the TOFA analogs described herein) through the skin barrier. They typically act to reduce the impedance or resistance of the skin to allow improved permeation of the therapeutic drugs. In particular, substances which would perturb the normal structure of the stratum corneum are capable of disrupting the intercellular lipid organization, thus reducing its effectiveness as a barrier.
  • penetration enhancers or permeation enhancers
  • lipids which would partition into the stratum comeum lipids causing a direct effect or any material which would effect the proteins and cause an indirect perturbation of the lipid structure.
  • solvents such as ethanol, can remove lipids from the stratum corneum, thus destroying its lipid organization and disrupting its barrier function.
  • penetration enhancers or barrier function disrupters include, but are not limited to, alcohol-based enhancers, such as alkanols with one to sixteen carbons, benzyl alcohol, butylene glycol, diethylene glycol, glycofurol, glycerides, glycerin, glycerol, phenethyl alcohol, polypropylene glycol, polyvinyl alcohol, and phenol; amide-based enhancers, such as N -butyl- N -dodecylacetamide, crotamiton, N,N -dimethylformamide, N,N -dimethylacetamide, N -methyl formamide, and urea; amino acids, such as L- ⁇ -amino acids and water soluble proteins; azone and azone-like compounds, such as azacycloalkanes; essential oils, such as almond oil, amyl butyrate, apricot kernel oil, avocado oil, camphor, castor oil, 1-carvone, coconut
  • Dermatologically effective amount refers to that amount of an active ingredient which, when administered dermatologically (i.e., systemically or locally, including, for example, topically, intradermally, intravenously, orally or by use of an implant, that afford administration to the sebaceous glands) to a human, is sufficient to effect the desired treatment, as defined below, of the disorder or condition of interest in the human.
  • the amount of an active ingredient which constitutes a “dermatologically effective amount” will vary depending on the active ingredient, the disorder or condition and its severity, and the age of the human to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • “Mammal” includes humans and both domestic animals such as laboratory animals and household pets, (e.g. cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildelife and the like.
  • Optional or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • substitutents on the functional group are also “optionally substituted” and so on, for the purposes of this invention, such iterations are limited to five, preferably such iterations are limited to two.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • Particularly preferred organic bases are isoprop
  • a “pharmaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans.
  • a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
  • “Therapeutically effective amount” refers to that amount of a compound of the invention which, when administered to a mammal, preferably a human, is sufficient to effect treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or condition.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease or condition and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • a “therapeutically effective amount” is that amount of a compound of invention which is sufficient to inhibit sebaceous gland activity.
  • Treating covers the treatment of the disease or condition of interest in a mammal, preferably a human, and includes:
  • the terms “disease” and “condition” may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
  • the compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centres and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as ( R )- or ( S )- or, as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), ( R )- and ( S )-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallisation.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
  • R 1 is the -O-R 3 -OC(O)-N(R 5 )R 6 group.
  • the formula for this group can be drawn as follows:
  • a compound of formula (I) wherein R 1 3-morpholinopropoxy i.e., a compound of the following formula: is named herein as 3-morpholinopropyl 5-(tetradecyloxy)furan-2-carboxylate.
  • one embodiment is a compound of formula (I) wherein: R 1 is -O-R 2 ; and R 2 is haloalkyl or substituted aryl.
  • one embodiment is a compound of formula (I) selected from: 2,2,2-trifluoroethyl 5-(tetradecyloxy)furan-2-carboxylate; 2,2,2-trichloroethyl 5-(tetradecyloxy)furan-2-carboxylate; 2-bromoethyl 5-(tetradecyloxy)furan-2-carboxylate; and 2-(5-(tetradecyloxy)furan-2-carbonyloxy)benzoic acid.
  • R 1 is -O-R 3 -OR 2 ;
  • R 2 is optionally substituted heterocyclylalkyl;
  • R 3 is an optionally substituted alkylene chain.
  • one embodiment is a compound of formula (I) which is 3-(tetrahydro-2H-pyran-2-yloxy)propyl 5-(tetradecyloxy)furan-2-carboxylate.
  • R 1 is -O-R 3 -OC(O)-N(R 5 )R 6 ; each R 2 is independently alkyl, haloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl or optionally substituted substituted heteroarylalkyl; R 3 is an optionally substituted alkylene chain; and R 5 is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted aralkyl; and R 6 is alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl or -R 3 -C(O)OR 3 ; and or any R 5 and R 6 , together with the nitrogen to which they are both attached, form an optional
  • one embodiment is a compound of formula (I) selected from:
  • one embodiment is a compound of formula (I) selected from:
  • one embodiment is a compound of formula (I) selected from:
  • one embodiment is a compound of formula (I) which is 5-(tetradecyloxy)- N -tosylfuran-2-carboxamide.
  • the pharmaceutical composition is a dermatological composition comprising a dermatologically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a dermatologically acceptable excipient.
  • the dermatological composition is a gel formulation, an alcoholic gel formulation, a hydroalcoholic gel formulation, or a cream formulation.
  • the pharmaceutical composition is an oral composition comprising a dermatologically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.
  • one embodiment of this method is wherein the dermatological disorder or condition is selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin.
  • Another embodiment of this method is wherein the dermatological disorder is acne.
  • Another embodiment of this method is wherein the dermatological disorder is oily skin.
  • Another embodiment of this method is wherein the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered topically.
  • Another embodiment of this method is wherein the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered systemically.
  • Another embodiment of this method is wherein the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered orally.
  • one embodiment of this method is wherein the dermatological disorder or condition is selected from the group consisting of acne vulgaris, acne conglobata, choracne, rosacea, Rhinophyma-type rosacea, seborrhea, seborrheic dermatitis, sebaceous gland hyperplasia, Meibomian gland dysfunction of facial rosacea, mitogenic alopecia, and oily skin.
  • Another embodiment of this method is wherein the dermatological disorder is acne.
  • Another embodiment is of this method wherein the dermatological condition is oily skin.
  • Another embodiment of this method is wherein the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered topically.
  • Another embodiment of this method is wherein the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered systemically.
  • Another embodiment of this method is wherein the therapeutically effective amount of a compound of formula (I), as set forth above, or a pharmaceutically acceptable salt thereof, is administered orally.
  • Another embodiment of this method is wherein the pharmaceutical composition is a dermatological composition and the pharmaceutically acceptable excipient is a dermatologically acceptable excipient.
  • Another embodiment of this method is wherein the pharmaceutical composition is a systemic composition.
  • Another embodiment of this method is wherein the pharmaceutical composition is an oral composition.
  • the method comprises administering to the human in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as set forth above in the Summary of the Invention, one embodiment of this method is wherein the therapeutically effective amount is administered topically.
  • Another embodiment of this method is wherein the therapeutically effective amount is administered systemically.
  • Another embodiment of this method is wherein the therapeutically effective amount is administered orally.
  • the method comprises administering to the human in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, as set forth above in the Summary of the Invention, one embodiment of this method is wherein the therapeutically effective amount of a compound of formula (I), as set forth above, or a pharmaceutically acceptable salt thereof, is administered topically.
  • Another embodiment of this method is wherein the pharmaceutical composition is administered systemically.
  • Another embodiment of this method is wherein the pharmaceutical composition is administered orally.
  • Another embodiment of this method is wherein the pharmaceutical composition is a dermatological composition and the pharmaceutically acceptable excipient is a dermatologically acceptable excipient.
  • Another embodiment of this method is wherein the pharmaceutical composition is a systemic composition.
  • Another embodiment of this method is wherein the pharmaceutical composition is an oral composition.
  • one embodiment of this method is wherein the disorder or condition is inflammatory acne.
  • Another embodiment of this method is wherein the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered topically.
  • Another embodiment of this method is wherein the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered systemically.
  • Another embodiment of this method is wherein the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered orally.
  • Another embodiment of this method is wherein the pharmaceutical composition is a dermatological composition and the pharmaceutically acceptable excipient is a dermatologically acceptable excipient.
  • Another embodiment of this method is wherein the pharmaceutical composition is a systemic composition.
  • Another embodiment of this method is wherein the pharmaceutical composition is an oral composition.
  • one embodiment of this method is wherein the disorder or condition is inflammatory acne.
  • Another embodiment of this method is wherein the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered topically.
  • Another embodiment of this method is wherein the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered systemically.
  • Another embodiment of this method is wherein the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered orally.
  • Another embodiment of this method is wherein the pharmaceutical composition is a dermatological composition and the pharmaceutically acceptable excipient is a dermatologically acceptable excipient.
  • Another embodiment of this method is wherein the pharmaceutical composition is a systemic composition.
  • Another embodiment of this method is wherein the pharmaceutical composition is an oral composition.
  • sebum Increased sebum production due to sebaceous gland hyperactivity is one of several factors generally believed to be contributors to acne pathogenesis.
  • sebum there is stepwise differentiation of sebocytes, a specialized epithelial cell type, arising from basal progenitor cells leading to lipid-forming cells which as they progress toward the gland outlet. These enlarged cells ultimately rupture (holocrine secretion) releasing their lipid-rich content (sebum).
  • the overall makeup of sebum consists of squalene (12%), cholesterol (2%), wax esters (26%), and diglycerides/triglycerides/free fatty acids (57%) (see, Zouboulis et al., "An oral 5-lipoxygenase inhibitor, directly reduces sebum production”. Dermatology. (2005) 210:36-38 ). Free fatty acid levels may be increased by bacterial degradation of the di- and triglycerides present within sebum (see, Thiboutot D. "Regulation of human sebaceous glands" J. Invest Dermatol. (2004) 123:1-12 ).
  • Free fatty acids may also promote the inflammatory aspects of acne by activating local immune cells and their release of a variety of pro-inflammatory factors.
  • ACC acetyl CoA carboxylase
  • ACC1 is present within the cytosol while ACC2 localizes to mitochondria.
  • ACC1 is responsible for long-chain fatty acid synthesis while mitochondrial ACC2 acts to inhibit fatty acid oxidation.
  • Expression of the ACC isoforms is tissue-specific and responsive to hormones and nutritional status.
  • ACC1 is expressed at high levels in lipogenic tissues, notably in adipose, liver, and lactating mammary gland.
  • ACC2 is a minor component of hepatic ACC and is the predominant isoform expressed, albeit at relatively low levels, in heart and skeletal muscle.
  • Active ACC has been shown to be present in human sebaceous glands, although the ACC isoform expression pattern has not yet been described (see, Smythe, C.D. et al., "The activity of HMG-CoA reductase and acetyl-CoA carboxylase in human apocrine sweat glands, sebaceous glands, and hair follicles is regulated by phosphorylation and by exogenous cholesterol, " J. Invest. Dermatol. (1998) 111:139-148 ).
  • ACC and other fatty acid and cholesterol synthesis-regulating enzymes have been shown to be positively regulated by androgen, a key factor contributing to the increased sebum production at puberty as well as the expression of acne (see, Rosignoli, C. et al., "Involvement of the SREBP pathway in the mode of action of androgens in sebaceous glands in vivo", Exp. Dermatol. (2003) 12:480-489 ).
  • ACC also catalyzes the first committed and regulated step in fatty acid synthesis in bacteria. Since membrane lipid biogenesis is essential for bacterial growth, inhibition of ACC activity may potentially decrease the growth of bacteria normally present within a comedone.
  • TOFA (tetradecyloxy)-2-furancarboxylic acid) is a known hypolipidemic compound having the following structure:
  • TOFA and pharmaceutically acceptable salts thereof are described and claimed in U.S. Patent No. 4,110,351 .
  • TOFA has been shown to reduce plasma triglyceride levels in both rats and monkeys (see, e.g., Parker, R.A. et al., J. Med. Chem. (1977), Vol. 20, pp. 781-791 ) and to inhibit hepatic fatty acid synthesis (see, e.g., Ribereau-Gayon, G., FEBS Lett. (1976), Vol. 62, No. 309-312 ; Panek, E. et al., Lipids (1977), Vol. 12, pp. 814-818 ; Kariya, T. et al., Biochem.
  • TOFA when converted intracellularly to its acyl-CoA thioester, inhibits ACC activity with a mechanism similar to long chain fatty acyl-CoA's, the physiological end-product inhibitors of ACC (see, McCune, S.A. et al., J. Biol. Chem. (1979), Vol. 254, No. 20., pp. 10095-10101 .
  • TOFA may exert multiple effects in sebaceous gland disorders by lowering sebum production and potentially affecting the growth of pathogenic bacteria at the treatment site.
  • Analogs of TOFA such as the compounds of the invention, are disclosed herein as effective inhibitors of sebaceous gland activity, and are therefore useful in treating a mammal, preferably a human, having a dermatological disorder or condition characterized by sebaceous gland hyperactivity, such as acne.
  • the analogs of TOFA disclosed herein may also be useful in treating a mammal having a disorder or condition characterized by inflammation by reducing T cell proliferation and cytokine secretion.
  • Suitable protecting groups include hydroxy, amino, mercapto and carboxylic acid.
  • Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl ( e.g. , t -butyldimethylsilyl, t -butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups for amino, amidino and guanidino include t -butoxycarbonyl, benzyloxycarbonyl, and the like.
  • Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters.
  • Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein.
  • the use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organic Synthesis (2006), 4th Ed., Wiley .
  • the protecting group may also be a polymer resin such as a Wang resin or a 2-chlorotrityl-chloride resin.
  • starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, e.g., Smith, M.B. and J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000 )) or prepared as described herein.
  • TOFA is commercially available, for example, from Cedarlane Laboratories, Inc.
  • the compounds of the present invention can be prepared as in Reaction Scheme 1, where R 2 , R 4 and R 5 are each as described above in the Summary of the Invention, by activating the carboxylic group of 5-(tetradecyloxy)furan-2-carboxylic acid (TOFA) with a suitable reagent including but not limited to: oxalyl chloride, thionyl chloride, acetic anhydride, trifluoroacetic anhydride, toluenesulfonyl chloride, hydroxysuccinamide, hydroxybenzotriazole, dicyclohexylcarbodiimide, or carbonyldiimidazole.
  • TOFA 5-(tetradecyloxy)furan-2-carboxylic acid
  • the activated acid compound is generally prepared at temperatures of between 0 °C and ambient and may be isolated or may be reacted in situ with a suitable alcohol or sulfonamide in the presence of a base (triethylamine, pyridine, etc.).
  • a base triethylamine, pyridine, etc.
  • the product from the reaction can be isolated and purified employing standard techniques such as solvent extraction, chromatography, crystallization, distillation, and the like.
  • the compounds of the present invention can also be prepared as outlined in Reaction Scheme 2 where each R 2 , R 3 , R 5 and R 6 are as described above in the Summary of the Invention.
  • TOFA can be reacted with an alkylating agent (either purchased commercially or prepared using techniques well known in the art) having a suitable leaving group (halide, triflate, tosylate, mesylate, and the like) in the presence of a suitable base (including but not limited to potassium carbonate, cesium carbonate, tetrabutylammonium hydroxide, triethylamine, etc.).
  • the reactions can be carried out in a suitable solvent such as N,N- dimethylformamide and are usually performed at a temperature between ambient and 70 °C.
  • the product from the reaction can be isolated and purified employing standard techniques such as solvent extraction, chromatography, crystallization, distillation, and the like.
  • the compounds of the present invention can also be prepared as shown above in Reaction Scheme 3.
  • TOFA can be reacted with a linker containing two suitable leaving groups (halide, triflate, tosylate, mesylate, and the like).
  • the initial reaction is performed as in Reaction Scheme 2 above.
  • the product of this reaction is then reacted with a suitable nucleophile including but not limited to amines (shown above), alcohols or phenols in a suitable solvent such as DMF or THF.
  • the reaction is generally performed at ambient temperature for 12 hrs in the presence of a suitable base which may be tetrabutylammonium hydroxide, excess of the amine nucleophile, triethylamine, or the like.
  • the product from the reaction can be isolated and purified employing standard techniques such as solvent extraction, chromatography, crystallization, distillation, and the like.
  • the final product of the Reaction Schemes shown above may be further modified, for example by manipulation of substituents.
  • manipulations may include, but are not limited to, oxidation, reduction, alkylation, acylation and hydrolysis, as needed to prepare the compounds of the invention.
  • Such manipulations are within the knowledge of one skilled in the organic chemistry field.
  • manipulations may also include the removal of a protecting group such as a Boc group, a tetrahydropyran group or the like by methods outlined in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Second Edition, John Wiley and Sons, New York, 1991 .
  • the biphasic mixture was transferred to a seperatory funnel and the organic phase was extracted 3 times with brine (3 x 10 mL). The organic phase was dried and concentrated to give a colourless oil. The resulting crude material was purified by flash chromatography eluting with 5-20% EtOAc in hexanes to yield a colourless syrup that solidified on standing.
  • N-benzyl-2-chloro-N-methylacetamide (0.250 g) was dissolved in 10 mL of N,N -dimethylformamide. To this solution were added 5-(tetradecyloxy)furan-2-carboxylic acid (0.180 g, 0.544 mmol), tetrabutylammonium hydroxide pentahydrate (0.209 g, 0.554 mmol), and sodium iodide ( ⁇ 15 mg). The suspension was heated to 60 °C with stirring for 14 hrs. The reaction was quenched with brine (5 mL), water (5 mL) and EtOAc (40 mL).
  • the title compound was prepared as in Example 20, Steps 1 and 2 starting with 0.324 g (2.0 mmol) of 1-phenyl piperazine and 0.160 mL (2 mmol) of chloroacetyl chloride except that the reaction mixture in Step 1 was diluted in EtOAc rather than hexanes.
  • the title compound was further purified by recrystallization from isopropanol and water.
  • Step 2 The title compound was prepared as in Example 20, Steps 1 and 2 starting with 0.198 mL (2.0 mmol) of piperidine and 0.160 mL (2 mmol) of chloroacetyl chloride except that the reaction mixture in Step 1 was diluted in EtOAc rather than hexanes.
  • the crude material isolated in Step 2 was purified by recrystallization from isopropanol.
  • Example 30 The title compound was prepared as in Example 30 starting with 0.335 g (1.5 mmol) of 2-(3-bromopropoxy)tetrahydro-2H-pyran and 0.162 g (0.5 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid.
  • 1 H NMR 300 MHz, CDCl 3 ) ⁇ : 7.15 (d, 1H), 5.30 (d, 1H), 4.59-4.62 (m, 1H), 4.40 (app t, 2H), 4.10 (t, 2H), 3.80-3.90 (m, 2H), 3.40-3.60 (m, 2H), 2.05 (p, 2H), 1.20-1.85 (m, 30H), 0.89 (t, 3H).
  • Example 30 The title compound was prepared as in Example 30 starting with 0.224 g (1.2 mmol) of 4-(2-chloroethyl)morpholine hydrochloride and 0.162 g (0.5 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid with the exception that a total of 0.730 g of cesium carbonate was added to neutralize the hydrochloride.
  • SZ95 sebocytes were prepared using human facial sebaceous gland cells transfected with a plasmid containing the coding region for the Simian virus-40 large T antigen (see, Zouboulis, C.C. et al., J. Invest. Dermatol. (1999), Vol. 113, pp. 1011-1020 ). SZ95 cells express a number of molecules typically associated with human sebocytes.
  • SZ95 cells are capable of recapitulating many aspects of sebocyte growth and differentiation (see, Wrobel, A. et al., "Differentiation and apoptosis in human immortalized sebocytes", J. Invest Dermatol. (2003) 120:175-181 ).
  • SZ95 cells can be used to identify compounds with sebum-inhibitory potential, such as Accutane® and cholesterol synthesis inhibitors (statins), both of which demonstrated the ability to lower lipid production by these cells (See, Tsukada, M. et al., "13-cis retinoic acid exerts its specific activity on human sebocytes through selective intracellular isomerization to all-trans retinoic acid and binding to retinoid acid receptors", J. Invest. Dermatol. (2000) 115:321-327 ).
  • compositions of the invention may also inhibit several parameters related to T cell activation including proliferation and secretion of immune/inflammation-regulating cytokines. Accordingly, analogs of TOFA would be useful agents in treating dermatological disorders or conditions characterized by inflammation, by reducing T cell proliferation and cytokine secretion, for example, in the treatment of inflammatory acne.
  • In vivo testing for evaluating potential acne treatment can be conducted using the following hamster assays because hamster ear sebaceous glands have a close resemblance to those of humans in terms of structure, biochemistry and physiology.
  • the Syrian golden hamster (Oryctolagus cuniculus) ear sebaceous gland model was used to evaluate the effect of repeat application of TOFA and TOFA analogs. Male animals were employed since they have larger sebaceous glands than females a consequence of their higher endogenous levels of androgenic hormones. To define compound effects, cross-sections prepared from hamster ears were treated with the neutral lipid-specific stain Oil Red O. Staining results were compared to the untreated ear of the same animal in order to account for any changes in the overall physiological state of the animal as well as potential systemic effects stemming from local drug application.
  • DMA dimethyl acetamide
  • acetone acetone/30% ethanol
  • Animals were typically 10-12 weeks of age and 100-150 g bodyweight at the start of the experiment.
  • Treatment groups consisted of 5-8 animals.
  • Non-anesthetized hamsters were administered the test material onto the ventral surface of the right ear using a pipette at a volume of 20 ⁇ l per ear. Materials were gently massaged into the treatment site with a gloved finger for approximately 15 sec.
  • Hamsters received treatment once daily for 15-28 consecutive days. Application of the test articles occurred within the same 4-hour period on each application day. The left ear remained untreated and served as an internal control site. Animals were evaluated daily for general appearance and potential clinical signs related to treatment such as edema, erythema, discoloration or other changes to the ears. Hamsters were also assessed for general health by coat appearance, behavior, and activity level.
  • Tissue samples for sebaceous gland analysis were subsequently taken by histology personnel.
  • the right (treated) and left (untreated) ears were carefully removed from euthanized hamsters.
  • a 3.5 mm punch biopsy of the treated ear was marked with a marking dye on the ventral surface.
  • a punch biopsy of the untreated ear was marked with a separate tissue-marking dye on the ventral surface.
  • Tissues were embedded in a labeled mold filled with "Neg 50" cryo-embedding medium and frozen on liquid nitrogen. These blocks were sequentially wrapped in Parafilm® then aluminum foil for storage at -70°C until required.
  • ear cross-sections were initially cut at a thickness of approximately 8 ⁇ m onto glass slides and immediately fixed with 10% buffered formalin. Sections were stained with the lipid-specific Oil Red O dye by standard methods, covered with Faramount (Dakocytomation, Ca) acrylic mounting medium, cover slipped and then allowed to set.
  • a Tissue sections stained with Oil Red O were viewed with a Spot RT digital camera mounted on an Olympus BX60 microscope.
  • Tissue sections stained with Oil Red O were viewed with a Spot RT digital camera mounted on an Olympus BX60 microscope. An image of the section was taken using the 4x microscope objective. The image was saved using the unique animal identification number, slide number, and magnification.
  • Relative sebaceous gland areas were determined using Image-Pro software (Media Cybernetics Inc., Silver Spring, MD). The area of image analysis was the dermis which included the region from the epidermal-dermal junction to the midline of the tissue demarcated by the central cartilage line. Data was expressed as percentage of the area of the tissue cross section which was red in color, representative of lipid-containing structures, in comparison to the total area analyzed.
  • Biological Examples may be used by one skilled in the art to determine the effectiveness of the compounds of the invention in treating a human having a dermatological disorder or condition characterized by sebaceous gland hyperactivity, in inhibiting sebaceous gland activity in a human, or in reducing T cell proliferation and cytokine secretion.
  • the immortalized human sebocyte cell line, SZ95 was maintained in culture as described in Zouboulis, C.C. et al., J. Invest. Dermatol. (1999), Vol. 113, pp. 1011-1020 . Lipid synthesis was stimulated by treating SZ95 cells with arachidonic acid (AA).
  • AA arachidonic acid
  • test compounds were dissolved in dimethylsulfoxide (DMSO) and added at the desired concentration in 96-well microtiter plates. The cells were then cultured for up to 72 hours before the plates were washed 3 times with PBS and a final volume of 200 ⁇ L PBS / well was added.
  • DMSO dimethylsulfoxide
  • test compound was dissolved in dimethylsulfoxide (DMSO) and added at the desired concentration to cells seeded into 96-well plates.
  • the cells were cultured for 48 hours in the presence of the test compound before the plates were washed 3 times with PBS.
  • a final volume of 100 ⁇ L of culture medium per well was added.
  • Twenty ⁇ L of MTS solution (0.2 mg/mL in sterile PBS) was added to each well and incubated for a minimum of 60 minutes until the desired optical density was reached.
  • the color development of the wells was measured using a plate reader at an absorbance of 590 nm. Effect on cell viability by the test compound was expressed as the % reduction of the absorbance for AA-stimulated cells in the presence of the test compound relative to the values obtained for the untreated control cells.
  • the human prostate LNCaP adenocarcinoma cell line can be obtained from American Type Culture Collection. Cells are maintained in RPMI 1640 medium containing 10% fetal calf serum (FCS), 4 mM Glutamax, 1 mM sodium pyruvate, 1 mM HEPES, penicillin (100 U/mL) and streptomycin (100 ⁇ g/mL). For experiments, approximately 10,000 cells/well are plated in 6-well tissue culture plates in RPMI 1640 10% FBS for 72 hours. To minimize potential serum androgen effects, medium containing 5% charcoal/dextran-stripped FCS is added for 72 hours.
  • FCS fetal calf serum
  • Lipid synthesis is then stimulated by addition of the androgen dihydrotestosterone (DHT) at 50 nM.
  • DHT androgen dihydrotestosterone
  • a compound of the invention is solubilized in DMSO and added at various concentrations in RPMI 1640 containing 5% charcoal/dextran-treated. Cells are incubated in the presence of these factors for 96 hours at 37°C. Lipid accumulation is subsequently quantified by Nile Red staining and flow cytometric analysis. The lipid level of test compound-treated wells is compared to the result obtained for the vehicle-treated cells.
  • Mouse 3T3-L1 preadipocytes (American Type Culture Collection) are passaged and maintained in Dulbecco's modified Eagles Medium (DMEM) supplemented with 10% fetal calf serum (FCS), 1 mM sodium pyruvate, penicillin (100U/ml)/sireptomycin (100 ⁇ g/ml) and 4 mM Glutamax (Gibco/Life Technologies).
  • DMEM Dulbecco's modified Eagles Medium
  • FCS fetal calf serum
  • penicillin 100U/ml
  • sireptomycin 100 ⁇ g/ml
  • 4 mM Glutamax Gibco/Life Technologies
  • Initiation medium consists of DMEM with 0.5 mM 3-isobutyl-1-methylxanthine, 1 ⁇ M dexamethasone and human insulin at 10 ⁇ g/ml.
  • Progression medium contains insulin (10 ⁇ g/ml) which replaces the initiation medium after 48-72 hours.
  • Cellular lipid is imaged by Oil Red O staining.
  • PBMC are isolated from different donors by density gradient centrifugation. Different amounts of a compound of the invention are added to PBMC cultures in the presence of two different stimuli sets.
  • One activating stimulus is phytohemagglutinin (PHA), a plant-derived mitogen that stimulates proliferation and cytokine synthesis by T lymphocytes.
  • PHA phytohemagglutinin
  • IFN- ⁇ interferon- ⁇
  • LPS lipopolysaccharide
  • Cytokine levels are interpolated from a standard curve generated in parallel.
  • Cell viability is assessed using a colorimetric assay based on the conversion of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) into a soluble formazan product by mitochondrial dehydrogenase of viable cells.
  • MTS inner salt
  • Cell proliferation is determined by adding 3 H-thymidine to the cultures and determining its level of incorporation into DNA using scintillation counting.
  • Table 1 shows that Compounds A, B and C exhibited considerably lower meting points and far greater solubility in liquid synthetic sebum than TOFA, which properties could promote their associations with the skin and delivery into the lipid-rich environment of the sebaceous glands.
  • TABLE 1 Compound Molecular weight (Daltons) Melting Point (°C) Solubility in Liquid Synthetic Sebum (mg/ml) TOFA 324.5 119 1.5 ⁇ 0.4
  • Compound B 366.5 ⁇ 22 43.0 ⁇ 0.5
  • the compound of the invention TOFA and vehicle were applied onto male hamster ears.
  • the hamsters were sacrificed and the area of sebaceous glands in the treated area was determined.
  • the untreated ear in this test system acted as an assay internal control as well as a means to detect potential systemic treatment effects.
  • This hamster assay evaluated the effect of topical application of TOFA in parallel with three compounds of the invention (Compounds A, B and C) on hamster ear sebaceous glands. Test compounds were applied topically daily at 75 mM for 21 days in 40% DMA/30% acetone/30% ethanol.
  • Compound A when tested in this assay, demonstrated the ability to reduce sebaceous gland area when compared to TOFA and when compared to vehicle.
  • This example assessed hamster sebaceous gland size after 21 days of application of Compound A as well as one and two weeks following cessation of treatment.
  • Compound A was applied in a mixture of 40% DMA/30% acetone /30% ethanol.
  • One-week and two-week follow-up sampling times were included to assess sebaceous gland recovery characteristics following the treatment.
  • a significant reduction in gland size was again produced with 21 days of Compound A treatment (shown in Figure 2 ).
  • average gland area was 63.5% lower for hamsters treated with Compound A.
  • sebaceous gland counts for ears exposed to Compound A were significantly lower than control values. This finding suggests a relatively sustained inhibitory effect on gland activity following treatment of the TOFA analogs described herein. Moreover, the finding suggests that an exaggerated rebound effect may not occur after cessation of a treatment regimen.
  • Figure 3 shows the histological appearance of ear cross-sections prepared in a study in which animals were treated for 21 consecutive days with control vehicle (40% DMA/30% acetone/30% ethanol), TOFA and Compound A at a concentration of 75 mM in a mixture. No appreciable inflammatory cell presence evident for skin sections prepared from the ears of hamsters treated with the control, TOFA and Compound A.
  • Sections were treated with Oil Red O to detect neutral lipids and counter-stained with hematoxylin. Images are orientated with the ventral ear surface positioned upwards. Reduced sebaceous gland area is evident in the section prepared from a Compound A -treated hamster. In comparison to vehicle-treated controls, epidermal thickness is greater for samples obtained from hamsters treated with TOFA or Compound A.
  • compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient are one aspect of the present invention.
  • These pharmaceutical compositions may be in any form which allows for the active ingredient, i.e. , a compound of formula (I), to be administered to a human in a therapeutically effective amount.
  • the pharmaceutical composition may be in the form of a semi-solid (gel), solid, liquid or gas (aerosol).
  • Typical routes of administration include, without limitation, systemic (including oral and parenteral), topical, buccal, transdermal, sublingual, nasal, rectal, vaginal, and intranasal administration.
  • parenteral as used herein includes subcutaneous injections, needle-less injections, intravenous, intramuscular, epidural, intrasternal injection or infusion techniques.
  • Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a human.
  • Pharmaceutical compositions of the invention that will be administered to a human may take the form of one or more dosage units, where for example, a tablet, capsule, cachet or patch may be a single dosage unit, and a container of a pharmaceutical composition of the invention in aerosol form may hold a plurality of dosage units.
  • the compound of formula (I) is preferably administered to the skin ( i.e ., topically) of the human in need thereof in dermatologically acceptable compositions, as described in more detail below.
  • dermatologically acceptable compositions e.g., when a dermatological composition comprising a compound of formula (I) and a dermatologically acceptable excipient is placed upon the skin of the human in need thereof
  • the compound of formula (I) is in continuous contact with the skin of the patient, thereby effecting treatment.
  • any suitable amount of a compound of formula (I) can be employed in such dermatological compositions, provided the amount employed effectively inhibits the production of sebum from sebocytes and remains stable in the composition over a prolonged period of time.
  • the stability is over a prolonged period of time, e.g., up to about 3 years, up to 1 year, or up to about 6 months, which is typical in the manufacturing, packaging, shipping and/or storage of dermatologically acceptable compositions.
  • a compound of formula (I) can be in solution, partially in solution with an undissolved portion or completely undissolved suspension.
  • a compound of formula (I) can be present in a dermatological composition of the invention in a concentration range from about 0.001 wt.% to about 80 wt.%, from about 0.001 wt.% to about 50 wt.%, from about 0.001 wt.% to about 25 wt.%, or from about 0.001 wt.% to about 6 wt.% of the dermatological composition.
  • a compound of formula (I) can be present in a concentration range of from about 0.001 wt.% to about 10 wt.%, from about 0.1 wt.% to about 10 wt.% or from about 1.0 wt.% to about 5.0 wt.% of the dermatological composition.
  • a dermatological formulation of a compound of formula (I) to be administered topically contains (by weight) about 3% TOFA in about 40% dimethylacetamide (DMA) / 30% acetone / 30% ethanol.
  • a dermatological composition of the invention can be in the form of a solution, lotion, foam, gel, cream and/or ointment.
  • the dermatological composition will be a topical formulation, for example, a gel, foam, cream or ointment.
  • a dermatological composition of the invention can contain one or more "lipophilic solvent(s)" that acts as a carrier into the pilosebaceous unit.
  • a lipophilic solvent useful in the invention can be miscible with water and/or lower chain alcohols and have a vapor pressure less than water at 25 °C (- 23.8 mm Hg).
  • a lipophilic solvent useful in the invention can be a glycol, specifically propylene glycol.
  • the propylene glycol can be from the class of polyethylene glycols, specifically polyethylene glycols ranging in molecular weight from 200 to 20000.
  • the solvent would be part of a class of glycol ethers.
  • a lipophilic solvent of the invention would be diethylene glycol monoethyl ether (transcutol).
  • DGME diethylene glycol monoethyl ether
  • transcutol refers to 2-(2-ethoxyethoxy)ethanol ⁇ CAS NO 001893 ⁇ or ethyoxydiglycol.
  • a dermatological composition of the invention can also contain one or more "filler(s)" that has a vapor pressure greater than or equal to 23.8 mm Hg at 25 °C.
  • the filler should have a vapor pressure greater than or equal to the lipophilic solvent as to concentrate the compound of formula (I) on the skin.
  • Preferred concentration range of a single filler or the total of a combination of fillers can be from about 0.1 wt.% to about 10 wt. %, more preferably from about 10 wt. % to about 50 wt.%, more specifically from about 50 wt.% to about 95 wt.% of the dermatological composition.
  • Non-limiting examples for use herein include water and lower alcohols, including ethanol, 2-propanol and n-propanol. More preferably, the filler is water, ethanol and/or 2-propanol. Specifically, the filler would be ethanol and/or water.
  • a dermatological composition of the invention can also contain one or more "humectant(s)" used to provide a moistening effect.
  • the humectant remains stable in the composition. Any suitable concentration of a single humectant or a combination of humectants can be employed, provided that the resulting concentration provides the desired moistening effect.
  • the suitable amount of humectant will depend upon the specific humectant or humectants employed.
  • Preferred concentration range of a single humectant or the total of a combination of humectants can be from about 0.1 wt.% to about 70 wt.%, more preferably from about 5.0 wt.% to about 30 wt.%, more specifically from about 10 wt.% to about 25 wt.% of the dermatological composition.
  • Non-limiting examples for use herein include glycerin, polyhydric alcohols and silicone oils. More preferably, the humectant is glycerin, propylene glycol and/or cyclomethicone. Specifically, the filler would be glycerine and/or cyclomethicone.
  • a dermatological composition of the invention can also contain a gelling agent that increases the viscosity of the final solution.
  • the gelling agent can also act as an emulsifying agent.
  • the present dermatogological compositions can form clear gels and soft gels, which upon application to the skin can break down and deteriorate, affording gels that do not dry on the skin.
  • concentration and combination of gelling agents will depend on the physical stability of the finished product.
  • Preferred concentration range of a gelling agent can be from about 0.01 wt.% to about 20 wt.%, more preferably from about 0.1 wt.% to about 10 wt.%, more specifically from about 0.5 wt. % to about 5 wt.% of the dermatological composition.
  • Non-limiting examples for use herein include classes of celluloses, acrylate polymers and acrylate crosspolymers.
  • hydroxypropyl cellulose, hydroxymethyl cellulose, Pluronic PF127 polymer, carbomer 980, carbomer 1342 and carbomer 940 more preferably hydroxypropyl cellulose, Pluronic PF127 carbomer 980 and carbomer 1342, more specifically hydroxypropyl cellulose (Klucel® EF, GF and/or HF), Pluronic PF127, carbomer 980 and/or carbomer 1342 (Pemulen® TR-1, TR-2 and/or Carbopol® ETD 2020).
  • a dermatological composition of the invention can contain one or more antioxidants, radical scavengers, and/or stabilizing agents, preferred concentration range from about 0.001 wt.% to about 0.1 wt.%, more preferably from about 0.1 wt.% to about 5 wt.% of the dermatological composition.
  • Non-limiting examples for use herein include butylatedhydroxytoluene, butylatedhydroxyanisole, ascorbyl palmitate, citric acid, vitamin E, vitamin E acetate, vitamin E-TPGS, ascorbic acid, tocophersolan and propyl gallate. More specifically the anti-oxidant can be ascorbyl palmitate, vitamin E acetate, vitamin E-TPGS, vitamin E or butylatedhydroxytoluene.
  • a dermatological composition of the invention can also contain preservatives that exhibit anti-bacterial and/or anti-fungal properties. Preservatives can be present in a gelled dermatological composition of the invention to minimize bacterial and/or fungal over its shelf-life. Preferred concentration range of preservatives in a dermatological composition of the invention can be from about 0.001 wt.% to about 0.01 wt.%, more preferably from about 0.01 wt.% to about 0.5 wt.% of the dermatological composition.
  • Non-limiting examples for use herein include diazolidinyl urea, methylparaben, propylparaben, tetrasodium EDTA, and ethylparaben. More specifically the preservative would be a combination of methylparaben and propylparaben.
  • a dermatological composition can optionally include one or more chelating agents.
  • chelating agent or “chelator” refers to those skin benefit agents capable of removing a metal ion from a system by forming a complex so that the metal ion cannot readily participate in or catalyze chemical reactions.
  • the chelating agents for use herein are preferably formulated at concentrations ranging from about 0.001 wt.% to about 10 wt.%, more preferably from about 0.05 wt.% to about 5.0 wt.% of the dermatological composition.
  • Non-limiting examples for use herein include EDTA, disodium edeate, dipotassium edeate, cyclodextrin, trisodium edetate, tetrasodium edetate, citric acid, sodium citrate, gluconic acid and potassium gluconate.
  • the chelating agent can be EDTA, disodium edeate, dipotassium edate, trisodium edetate or potassium gluconate.
  • compositions of this invention can be provided in any cosmetically suitable form, preferably as a lotion or a cream, but also in an ointment or oil base, as well as a sprayable liquid form (e.g., a spray that includes TOFA in a base, vehicle or carrier that dries in a cosmetically acceptable way without the greasy appearance that a lotion or ointment would have when applied to the skin).
  • a sprayable liquid form e.g., a spray that includes TOFA in a base, vehicle or carrier that dries in a cosmetically acceptable way without the greasy appearance that a lotion or ointment would have when applied to the skin.
  • compositions of the invention can include one or more compatible cosmetically acceptable adjuvants commonly used, such as colorants, fragrances, emollients, humectants and the like, as well as botanicals, such as aloe, chamomile and the like.
  • the skin of the human to be treated can be optionally pre-treated (such as washing the skin with soap and water or cleansing the skin with an alcohol-based cleanser) prior to administration of the dermatological composition of the invention.
  • a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) can also be administered systemically, preferably orally, to the human in need thereof in pharmaceutically acceptable compositions, as described in more detail below.
  • a pharmaceutical composition of the invention to be orally administered can be prepared by combining a compound of formula (I) with an appropriate pharmaceutically acceptable carrier, diluent or excipient by standard methods known to one skilled in the art.
  • Pharmaceutical compositions of the invention are formulated so as to allow the compound of formula (I) contained therein to be bioavailable upon administration of the composition to a human.
  • a pharmaceutical composition of the invention to be orally administered may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form.
  • Such a solid composition will typically contain one or more inert diluents or edible carriers.
  • binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.
  • excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like
  • lubricants such as magnesium stearate or Sterotex
  • glidants such as colloidal silicon dioxide
  • sweetening agents such as sucrose or saccharin
  • a flavoring agent such as peppermint, methyl sal
  • a pharmaceutical composition of the invention is in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.
  • a pharmaceutical composition of the invention to be orally administered may also be in the form of a liquid, for example, an elixir, syrup, solution, emulsion or suspension.
  • the pharmaceutical composition may also optionally contain one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
  • Liquid pharmaceutical compositions of the invention may also include one or more of the following adjuvants: sterile water, saline solution (preferably physiological saline solution), Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • adjuvants sterile water, saline solution (preferably physiological saline solution), Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols,
  • a liquid pharmaceutical composition of the invention contains a therapeutically effective amount of a compound of formula (I) when administered to a human in need thereof. Typically, this amount is at least 0.01% of a compound of formula (I) in the composition. This amount may be varied to be between about 0.1 wt.% and about 70% of the total weight of the composition.
  • Preferred oral pharmaceutical compositions contain a compound of formula (I) at a concentration range of between about 1.0 wt.% and about 50 wt.% of the oral composition.
  • a pharmaceutical composition of the invention may include various materials, which modify the physical form of a solid or liquid dosage unit.
  • the composition may include materials that form a coating shell around the active ingredient.
  • the materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents.
  • the active ingredient may be encased in a gelatin capsule.
  • a pharmaceutical composition of the invention in solid or liquid form may also include an agent that binds to a compound of formula (I) and thereby assists in the systemic delivery of the compound of formula (I).
  • agents that may act in this capacity include a monoclonal or polyclonal antibody, a protein or a liposome.
  • Systemic administration of the pharmaceutical compositions of the invention also include administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as transdermal, transmucosal, or pulmonary administration and needle-less injection administration.
  • injection e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as transdermal, transmucosal, or pulmonary administration and needle-less injection administration.
  • Useful injectable pharmaceutical compositions include sterile suspensions, solutions or emulsions of the active compound(s) in aqueous or oily vehicles.
  • the compositions may also contain formulating agents, such as suspending, stabilizing and/or dispersing agent.
  • the pharmaceutical compositions for injection may be presented in unit dosage form, e.g., in ampules or in multidose containers, and may contain added preservatives.
  • the injectable pharmaceutical compositions may be provided in powder form for reconstitution with a suitable vehicle, including but not limited to sterile pyrogen free water, buffer, dextrose solution, etc., before use.
  • a suitable vehicle including but not limited to sterile pyrogen free water, buffer, dextrose solution, etc.
  • the active compound i.e. , a compound of formula (I)
  • the active compound may be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are known in the art.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof can be formulated as a depot preparation for administration by implantation or intramuscular injection.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof may be formulated with suitable polymeric or hydrophobic materials (e . g ., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e . g ., as a sparingly soluble salt.
  • transdermal delivery systems manufactured as an adhesive disc or patch which slowly releases a compound of formula (I), or a pharmaceutically acceptable salt thereof, for percutaneous absorption may be used.
  • permeation or penetration enhancers may be used to facilitate transdermal penetration of the active compound(s).
  • Suitable transdermal patches are described in for example, U.S. Pat. No. 5,407,713 ; U.S. Pat. No. 5,352,456 ; U.S. Pat. No. 5,332,213 ; U.S. Pat. No. 5,336,168 ; U.S. Pat. No. 5,290,561 ; U.S. Pat. No. 5,254,346 ; U.S. Pat. No. 5,164,189 ; U.S. Pat. No. 5,163,899 ; U.S. Pat. No. 5,088,977 ; U.S. Pat. No. 5,087,240 ; U.S. Pat. No. 5,008,110 ; and U.S. Pat. No. 4,921,475 .
  • compositions of the invention by needle-less injection can be employed using the techniques disclosed in U.S. Pat. No. 6,756,053 .
  • Liposomes and emulsions are well-known examples of delivery vehicles that may be used to deliver active compound(s) or prodrug(s).
  • Certain organic solvents such as dimethylsulfoxide (DMSO) may also be employed, although usually at the cost of greater toxicity.
  • DMSO dimethylsulfoxide
  • compositions of the invention may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active compound(s).
  • the pack may, for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • compositions of the invention as set forth above may be prepared by methodology well known in the pharmaceutical art or by the method described herein. See, for example, Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pennsylvania, 1990 ).
  • compositions of the invention are administered to a human in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the compound of formula (I); the metabolic stability and length of action of the compound of formula (I); the age, body weight, general health, sex, and diet of the human; the mode and time of administration; the rate of excretion; the drug combination; and the severity of the particular disorder or condition.
  • a therapeutically effective daily dose of a compound of formula (I) is (for a 70 kg mammal) from about 0.001 mg/kg ( i . e ., 0.07 mg) to about 100 mg/kg ( i.e.
  • a therapeutically effective dose is (for a 70 kg mammal) from about 0.01 mg/kg ( i.e. , 0.7 mg) to about 50 mg/kg ( i.e. , 3.5 gm); more preferably a therapeutically effective dose is (for a 70 kg mammal) from about 1 mg/kg ( i.e ., 70 mg) to about 25 mg/kg ( i.e. , 1.75 gm).
  • Formulation Examples 1-5 provide dermatological compositions of the invention comprising a representative compound of formula (I) and one or more dermatologically acceptable excipients.
  • the product of the following formulation is a semi-solid clear gel.
  • Ingredient Percent w/w Compound of formula (I) 1.0 Diethylene Glycol Monoethyl Ether, NF 32.0 Tocophersolan, NF 1.0 Hydroxypropyl Cellulose, NF (Klucel® GF) 4.0 Edetate Disodium 0.05 Alcohol, Dehydrated, NF 61.95
  • the above formulation may be prepared as follows. The alcohol and diethylene glycol monoethyl ether are combined. Tocophersolan, edetate disodium and the compound of formula (I) are dissolved with mixing. Hydroxypropyl cellulose is added and quickly and evenly dispersed with high-speed mixing. The product is removed from mixing after uniform dispersion.
  • the product of the following formulation is a semi-solid clear soft gel.
  • Ingredient Percent w/w Compound of formula (I) 1.0 Diethylene Glycol Monoethyl Ether, NF 30.0 Glycerin, USP 5.0 Tocophersolan, NF 1.0 Methylparaben, NF 0.1 Propylparaben, NF 0.02 Edetate Disodium 0.05 Acrylates/C10-C30 Alkyl Acrylate Crosspolymer, NF 2.0 Polysorbate 80, NF 0.1 Trolamine, NF to pH 6.75 Water, USP to 100.0
  • the above formulation may be prepared as follows. The liquids, diethylene glycol monoethyl ether, glycerin and water, are mixed. Polysorbate 80 and tocophersolan are added and mixed to dissolve. The compound of formula (I) is added and mixed to dissolve. Edetate disodium, methylparaben, and propylparaben are added and mixed to dissolve. Acrylates/C10-C30 alkyl acrylate crosspolymer are quickly dispersed with high-speed mixing until uniform mixture obtained. Trolamine is added with constant mixing to obtain a viscous gel at a pH of approximately 6.75 (when diluted 1:9 with water).
  • the product of the following formulation is a semi-solid clear soft gel.
  • Ingredient Percent w/w Compound of formula (I) 1.0 Diethylene Glycol Monoethyl Ether, NF 30.0 Alcohol, NF 25.0 Glycerin, USP 5.0 Tocophersolan, NF 1.0 Methylparaben, NF 0.1 Propylparaben, NF 0.02 Edetate Disodium 0.05 Hydroxypropyl Cellulose, NF (Klucel® EF) 2.0 Acrylates/C10-C30 Alkyl Acrylate Crosspolymer, NF 1.0 Polysorbate 80, NF 0.05 Trolamine, NF to pH 6.75 Water, USP to 100.0
  • the above formulation may be prepared as follows. The liquids, diethylene glycol monoethyl ether, glycerin alcohol and water, are mixed. Polysorbate 80 and tocophersolan are added and mixed to dissolve. The compound of formula (I) is added and mixed to dissolve. Edetate disodium, methylparaben and propylparaben are added and mixed to dissolve. Acrylates/C10-C30 alkyl acrylate crosspolymer and hydroxypropyl cellulose are quickly dispersed with high-speed mixing until uniform mixture obtained. Trolamine is added with constant mixing to obtain a viscous gel at a pH of approximately 6.75 (when diluted 1:9 with water).
  • a compound of formula (I) may also be formulated as a cream, an example of which is as follows: Ingredient Percent w/w Compound of formula (I) 1.0 Diethylene Glycol Monoethyl Ether, NF 20.0 White Petrolatum 5.0 Isopropyl Myristate 5.0 Cetostearyl Alcohol 5.0 Trilaureth-4 Phosphate 1.0 Tocophersolan, NF 1.0 Cyclomethicone, NF 5.0 Methylparaben, NF 0.2 Propylparaben, NF 0.04 Edetate Disodium 0.05 Carbomer 940 0.15 Acrylates/C10-C30 Alkyl Acrylate Crosspolymer, NF 0.15 Trolamine, NF to pH 6.75 Water, USP to 100.0
  • the above formulation may be prepared as follows:
  • White petrolatum, cyclomethicone, isopropyl myristate and cetostearyl alcohol are combined in a separate vessel and melted completely at a temperature of between about 65 °C and about 75 °C and stirred.
  • a compound of formula (I) may also be formulated as a foam, an example of which is as follows: Ingredient Percent w/w* Compound of formula (I) 1.0 Diethylene Glycol Monoethyl Ether, NF 25.0 Stearyl Alcohol, NF 8.0 Laureth-23 0.5 PEG-100 Stearate 1.0 Tocophersolan, NF 1.0 Propylparaben, NF 0.3 Edetate Disodium 0.05 Acrylates/C10-C30 Alkyl Acrylate Crosspolymer, NF 0.2 Trolamine, NF to pH 6.75 Water, USP to 100.0 *Propellant is 4.0 wt.% of final formulation.
  • the propellant is a single gas or a mixture of gases. Suitable gases include butane, isobutane, propane, isopropane and isopentate.
  • the above formulation may be prepared as follows:
  • Stearyl alcohol, laureth-23 and PEG-100 stearate are combined in a separate vessel and melted completely. while stirring, at a temperature of between about 60 °C and about 70 °C.
  • Compounds of the invention may be usefully combined with one or more other therapeutic agents in the treatment of dermatological disorders or conditions characterized by sebaceous gland hyperactivity.
  • a compound of the invention may be administered simultaneously, sequentially or separately in combination with other therapeutic agents, including, but not limited to:
  • “combination” refers to any mixture or permutation of a compound of the invention and one or more additional therapeutic agents useful in the treatment of dermatological disorders or conditions. Unless the context makes clear otherwise, “combination” may include simultaneous or sequentially delivery of a compound of the invention with one or more therapeutic agents. Unless the context makes clear otherwise, “combination” may include dosage forms of a compound of the invention (e . g ., dermatological or pharmaceutical compositions comprising a compound of the invention and a dermatological acceptable excipient) with another therapeutic agent. Unless the context makes clear otherwise, “combination” may include routes of administration of a compound of the invention with another therapeutic agent. Unless the context makes clear otherwise, “combination” may include compositions comprising a compound of the invention and another therapeutic agent. Dosage forms, routes of administration and dermatological and pharmaceutical compositions include, but are not limited to, those described herein.

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Claims (15)

  1. Verbindung der Formel (I):
    Figure imgb0043
     wobei:
    R1 -O-R2 ist, wobei R2 Haloalkyl oder substituiertes Aryl ist, oder
    R1 -O-R3-OR2 ist, wobei R2 wahlweise substituiertes Heterocyclylalky ist und R3 eine wahlweise substituierte Alkylen-Kette ist, oder
    R1 -O-R3-OC(O)-N(R5)R6, -O-R3-N(R5)R6, -O-R3-N(R4)C(O)OR5, -O-R3-C(O)OR5, -O-R3-C(O)N(R5)R6 oder -N(R5)S(O)2-R4 ist, wobei jedes R3 unabhängig eine wahlweise substituierte Alkylen-Kette ist, und
    R4 wahlweise substituiertes Alkyl, wahlweise substituiertes Aryl, wahlweise substituiertes Aralkyl, wahlweise substituiertes Heteroaryl oder wahlweise substituiertes Heteroarylalkyl ist,
    jedes R5 unabhängig Wasserstoff, Alkyl, wahlweise substituiertes Cycloalkyl, wahlweise substituiertes Aryl oder wahlweise substituiertes Aralkyl ist, und
    jedes R6 Alkyl, wahlweise substituiertes Cycloalkyl, wahlweise substituiertes Aralkyl oder -R3-C(O)OR4 ist,
    oder ein beliebiges R5 und R6 zusammen mit dem Stickstoff, an den sie beide gebunden sind, ein wahlweise substituiertes N-Heterocyclyl oder ein wahlweise substituiertes N-Heteroaryl bilden,
    als einzelnes Stereoisomer oder als Mischung davon,
    oder ein pharmazeutisch unbedenkliches Sanz davon.
  2. Verbindung nach Anspruch 1, wobei:
    R1 -O-R2 ist und
    R2 Haloalkyl oder substituiertes Aryl ist.
  3. Verbindung nach Anspruch 2, ausgewählt aus:
    2,2,2-Trifluorethyl 5-(tetradecyloxy)furan-2-carboxylat,
    2,2,2-Trichlorethyl 5-(tetradecyloxy)furan-2-carboxylat,
    2-Bromethyl 5-(tetradecyloxy)furan-2-carboxylat und
    2-(5-(Tetradecyloxy)furan-2-carbonyloxy)benzoesäure.
  4. Verbindung nach Anspruch 1, wobei:
    R1 -O-R3-OR2 ist,
    R2 wahlweise substituiertes Heterocyclylalkyl ist und
    R3 eine wahlweise substituierte Alkylen-Kette ist.
  5. Verbindung nach Anspruch 1, wobei:
    R1 -O-R3-OC(O)-N(R5)R6 ist,
    R3 eine wahlweise substituierte Alkylen-Kette ist und
    R5 Wasserstoff, Alkyl, wahlweise substituiertes Cycloalkyl, wahlweise substituiertes Aryl oder wahlweise substituiertes Aralkyl ist, und
    R6 Alkyl, wahlweise substituiertes Cycloalkyl, wahlweise substituiertes Aralkyl oder -R3-C(O)OR3 ist, und
    oder ein beliebiges R5 und R6 zusammen mit dem Stickstoff, an den sie beide gebunden sind, ein wahlweise substituiertes N-Heterocyclyl oder ein wahlweise substituiertes N-Heteroaryl bilden.
  6. Verbindung nach Anspruch 1, ausgewählt aus:
    3-(Tetrahydro-2H-pyran-2-yloxy)propyl 5-(tetradecyloxy)furan-2-carboxylat,
    2-(Dimethylamino)ethyl 5-(tetradecyloxy)furan-2-carboxylat,
    2-Morpholinoethyl 5-(tetradecyloxy)furan-2-carboxylat,
    3-Morpholinopropyl 5-(tetradecyloxy)furan-2-carboxylat,
    5-(Tetradecyloxy)-N-tosylfuran-2-carboxamid,
    1-(Benzyl(methyl)carbamoyloxy)ethyl 5-(tetradecyloxy)furan-2-carboxylat,
    1-((2-Ethoxy-2-oxoethyl)(methyl)carbamoyloxy)ethyl 5-(tetradecyloxy)furan-2-carboxylat,
    4 (2S)-2-Benzyl 1-(1-(5-(tetradecyloxy)furan-2-carbonyloxy)ethyl)pyrrolidin-1,2-dicarboxylat,
    1-(4-Phenylcyclohexancarbonyloxy)ethyl 5-(tetradecyloxy)furan-2-carboxyiat,
    1-(5-(Tetradecyloxy)furan-2-carbonyloxy)ethyl 3-phenylpyrrolidin-1-carboxylat,
    1-(5-(Tetradecyloxy)furan-2-carbonyloxy)ethyl 3,4-dihydroisochinolin-2(1 H)-carboxylat,
    1-(5-(Tetradecyloxy)furan-2-carbonyloxy)ethylpiperidin-1-carboxylat,
    1-(5-(Tetradecyloxy)furan-2-carbonyloxy)ethylmorpholin-4-carboxylat,
    1-tert-Butyl 4-(1-(5-(tetradeclyoxy)furan-2-carbonyloxy)ethyl)piperazin-1,4-dicarboxylat und
    1-(Dicyclohexylcarbamoyloxy)ethyl 5-(tetradecyloxy)furan-2-carboxylat.
  7. Verbindung nach Anspruch 1, wobei:
    R1 -O-R3-N(R5)R6 ist,
    R3 eine wahlweise substituierte Alkylen-Kette ist und
    R5 Wasserstoff, Alkyl, wahlweise substituiertes Cycloalkyl, wahlweise substituiertes Aryl oder wahlweise substituiertes Aralkyl ist und
    R6 Alkyl, wahlweise substituiertes Cycloalkyl, wahlweise substituiertes Aralkyl oder -R3-C(O)OR4 ist, und
    oder ein beliebiges R5 und R6 zusammen mit dem Stickstoff, an den sie beide gebunden sind, ein wahlweise substituiertes N-Heterocyclyl oder ein wahlweise substituiertes N-Heteroaryl bilden.
  8. Verbindung nach Anspruch 1, wobei:
    R1 -O-R3-C(O)N(R5)R6 ist,
    R3 eine wahlweise substituierte Alkylen-Kette ist und
    R5 Wasserstoff, Alkyl, wahlweise substituiertes Cycloalkyl, wahlweise substituiertes Aryl oder wahlweise substituiertes Aralkyl ist und
    R6 Alkyl, wahlweise substituiertes Cycloalkyl, wahlweise substituiertes Aralkyl oder -R3-C(O)OR4 ist,
    oder R5 und R6 zusammen mit dem Stickstoff, an den sie beide gebunden sind, ein wahlweise substituiertes N-Heterocyclyl oder ein wahlweise substituiertes N-Heteroaryl bilden.
  9. Verbindung nach Anspruch 8, ausgewählt aus:
    2-(Benzyl(methyl)amino)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylat,
    tert-Butyl 4-(2-(5-tetradecyloxy)furan-2-carbonyloxy)acetyl)piperazin-1-carboxylat,
    2-(Dicyclohexylamino)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylat,
    2-(4-Cyclohexylpiperazin-1-yl)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylat,
    2-Oxo-2-(4-phenylpiperzin-1-yl)ethyl-5-(tetradecyloxy)furan-2-carboxylat,
    2-((2-Ethoxy-2-oxoethyl)(methyl)amino)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylat,
    2-Oxo-2-(piperidin-1-yl)ethyl-5-(tetradecyloxy)furan-2-carboxylat,
    2-Morpholin-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylat,
    2-(3,4-Dihydroisochinolin-2(1 H)-yl)-2-oxoethyl 5-(tetradecyloxy)furan-2-carboxylat, und
    (S)-Benzyl 1-(2-(5-(tetradecyloxy)furan-2-carbonyloxy)acetyl)pyrrolidin-2-carboxylat.
  10. Verbindung nach Anspruch 1, wobei:
    R1 -N(R5)S(O)2-R4 ist,
    R4 wahlweise substituiertes Alkyl, wahlweise substituiertes Aryl, wahlweise substituiertes Aralkyl, wahlweise substituiertes Heteroaryl oder wahlweise substituiertes Heteroarylalkyl ist, und
    R5 unabhängig Wasserstoff, Alkyl, wahlweise substituiertes Cycloalkyl, wahlweise substituiertes Aryl oder wahlweise substituiertes Aralkyl ist.
  11. Pharmazeutische Zusammensetzung, umfassend:
    eine therapeutisch wirksame Menge einer Verbindung nach einem der Ansprüche 1 bis 11, oder eines pharmazeutisch unbedenklichen Salzes davon, und
    einen pharmazeutisch oder dermatologisch unbedenklichen Trägerstoff.
  12. Pharmazeutische Zusammensetzung nach Anspruch 11, wobei die pharmazeutische Zusammensetzung eine dermatologische Zusammensetzung zur Verwendung bei der Behandlung eines Menschen ist, der eine dermatologische Störung oder Erkrankung aufweist, die durch eine Talgdrüsen-Hyperaktivität gekennzeichnet ist.
  13. Pharmazeutische Zusammensetzung nach Anspruch 12, wobei die dermatologische Störung oder Erkrankung aus der Gruppe ausgewählt ist, die aus Acne vulgaris, Acne conglobata, Chlorakne, Rosazea, Rhinophym-Rosazea, Seborrhoe, seborrhoisches Ekzem, Talgdrüsen-Hyperplasie, Meibomdrüsen -Dysfunktion bei Rosazea des Gesichts, durch Milben ausgelöstem Haarausfall und fettiger Haut besteht.
  14. Pharmazeutische Zusammensetzung nach Anspruch 11 zur Verwendung bei der Hemmung der Talgdrüsenaktivität beim Menschen.
  15. Pharmazeutische Zusammensetzung nach Anspruch 11 zur Verwendung bei der Behandlung eines Menschen, der eine Störung oder Erkrankung aufweist, die durch Entzündung gekennzeichnet ist.
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Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8884034B2 (en) * 2009-07-08 2014-11-11 Dermira (Canada), Inc. TOFA analogs useful in treating dermatological disorders or conditions
US8927679B2 (en) * 2013-01-15 2015-01-06 Xerox Corporation Tuning toner gloss with bio-based stabilizers
CN105530940A (zh) 2013-09-12 2016-04-27 辉瑞大药厂 乙酰辅酶a羧化酶抑制剂用于治疗寻常痤疮的用途
AU2016215228A1 (en) * 2015-02-05 2017-08-10 Dermira Inc. Synthetic process for preparing 2-((2-ethoxy-2-oxoethyl)(methyl)amino)-2-oxoethyl 5-tetradecyloxy)furan-2-carboxylate
PL3253743T3 (pl) 2015-02-05 2020-03-31 Dermira, Inc. Syntetyczny sposób otrzymywania pochodnych kwasu 2-furanokarboksylowego
JP2019522016A (ja) * 2016-07-26 2019-08-08 デルミラ インコーポレーテッド ２−（２−エトキシ−２−オキソエチル）（メチル）アミノ−２−オキソエチル５−（テトラデシルオキシ）フラン−２−カルボキシレートの皮膚科学的製剤
WO2018170316A1 (en) * 2017-03-16 2018-09-20 The Board Of Trustees Of The Leland Stanford Junior University Methods of identifying myc-driven and lipogenesis-dependent neoplasms and methods of treating the same
US12011437B1 (en) 2017-06-07 2024-06-18 Arcutis Biotherapeutics, Inc. Roflumilast formulations with an improved pharmacokinetic profile
US11129818B2 (en) 2017-06-07 2021-09-28 Arcutis Biotherapeutics, Inc. Topical roflumilast formulation having improved delivery and plasma half life
US20210161870A1 (en) 2017-06-07 2021-06-03 Arcutis Biotherapeutics, Inc. Roflumilast formulations with an improved pharmacokinetic profile
US9895359B1 (en) 2017-06-07 2018-02-20 Arcutis, Inc. Inhibition of crystal growth of roflumilast
CA3068623A1 (en) 2017-06-30 2019-01-03 Quixgen, Inc. Novel spirolactone compounds
WO2019072478A1 (en) 2017-10-10 2019-04-18 Galderma Research & Development SPECIFIC ACETYL-COA CARBOXYLASE INHIBITORS FOR USE IN THE TREATMENT AND / OR PREVENTION OF ACNE
JP6950524B2 (ja) * 2017-12-28 2021-10-13 トヨタ自動車株式会社 ハイブリッド車両の制御装置
KR20210044191A (ko) 2018-06-04 2021-04-22 아큐티스, 인크. 로플루밀라스트 피부 침투 지연 시간의 개선 방법 및 제형
RU2678307C1 (ru) * 2018-11-13 2019-01-25 Индивидуальный предприниматель Талагаева Елена Владимировна Активная против акне добавка к парфюмерно-косметическим продуктам
CN109608415B (zh) * 2019-01-21 2020-12-01 暨南大学 噻唑甲酰胺类化合物及其合成和应用
US20200330429A1 (en) * 2019-04-22 2020-10-22 Nestlé Skin Health Sa Method of treating truncal acne with trifarotene
AU2021268977B2 (en) * 2020-05-07 2024-05-23 Arcutis Biotherapeutics, Inc. Treatment of skin conditions using high Krafft temperature anionic surfactants
CN114767665B (zh) * 2021-06-11 2023-10-10 同济大学 5-十四烷氧基-2-呋喃甲酸在制备用于治疗银屑病样皮炎的药物中的用途
DE102022201276A1 (de) 2022-02-08 2023-08-10 Beiersdorf Aktiengesellschaft Neue TOFA-Analoga, Zubereitungen zur Sebumreduktion mit einem Gehalt an solchen Analoga und die kosmetische und/oder therapeutische Verwendung solcher Analoga als wirksames Prinzip zur Sebumreduktion oder -verhinderung
DE102022201277A1 (de) 2022-02-08 2023-08-10 Beiersdorf Aktiengesellschaft Neue TOFA-Analoga, Zubereitungen zur Sebumreduktion mit einem Gehalt an solchen Analoga und die kosmetische und/oder therapeutische Verwendung solcher Analoga als wirksames Prinzip zur Sebumreduktion oder -verhinderung

Family Cites Families (192)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS502373B1 (de) 1969-08-18 1975-01-25
US4110351A (en) * 1973-04-02 1978-08-29 Richardson-Merrell Inc. Hypolipidemic agents RO- or RS- substituted furoic acids, esters and salts
US4602099A (en) 1973-04-02 1986-07-22 Merrell Dow Pharmaceuticals Inc. Antirhinovirus agents
US4093622A (en) 1975-05-19 1978-06-06 Zoecon Corporation Pyridine esters of cyclopropane-carboxylic acid
SU689180A1 (ru) * 1978-02-20 2006-12-27 Пермский ордена Трудового Красного Знамени государственный университет им. А.М.Горького β-(5-Бромфуроил)-β-фенилгидразиды диалкилгликолевых кислот, проявляющие противовоспалительную активность
US4935421A (en) 1981-11-12 1990-06-19 E. I. Du Pont De Nemours And Company 2-hydroxypropylamine aryl ester derivatives and pharmaceutical use
IT1140323B (it) 1981-12-09 1986-09-24 Montedison Spa Processo per la preparazione di composti carbossilati aromatici o etero-aromatici
US5087240A (en) 1983-08-18 1992-02-11 Drug Delivery Systems Inc. Transdermal drug patch with conductive fibers
US4921475A (en) 1983-08-18 1990-05-01 Drug Delivery Systems Inc. Transdermal drug patch with microtubes
US5163899A (en) 1987-03-20 1992-11-17 Drug Delivery Systems Inc. Transdermal drug delivery system
US5312325A (en) 1987-05-28 1994-05-17 Drug Delivery Systems Inc Pulsating transdermal drug delivery system
US5151424A (en) 1987-07-01 1992-09-29 Janssen Pharmaceutica N.V. Pharmacologically active (Bicyclic heterocyclyl)methyl and -hetero) substituted hexahydro-1H-azepines and pyrrolidines
US5256625A (en) 1987-08-13 1993-10-26 Monsanto Company Safening imidazolinone herbicides
US5710100A (en) 1987-08-13 1998-01-20 Monsanto Company Safening imidazolinone herbicides
GB8804164D0 (en) 1988-02-23 1988-03-23 Tucker J M Bandage for administering physiologically active compound
WO1989011535A1 (en) 1988-05-25 1989-11-30 The Queen's University Of Belfast Methylation of organic compounds
DE3829450A1 (de) 1988-08-31 1990-03-01 Hoechst Ag Nigericinderivate, verfahren zu deren herstellung, diese enthaltende mittel und verwendung derselben
DE3830509A1 (de) 1988-09-08 1990-03-22 Hoechst Ag Arzneimittel mit synergistischer antimykotischer und antiviraler wirksamkeit
US5008110A (en) 1988-11-10 1991-04-16 The Procter & Gamble Company Storage-stable transdermal patch
US5088977A (en) 1988-12-21 1992-02-18 Drug Delivery Systems Inc. Electrical transdermal drug applicator with counteractor and method of drug delivery
US4980371A (en) 1988-12-21 1990-12-25 Merrell Dow Pharmaceuticals Antiretroviral furan ketones
DE3907784A1 (de) 1989-03-10 1990-09-13 Hoechst Ag Heteroaryl-aryl-buten- und -butanderivate, verfahren zu ihrer herstellung, sie enthaltende mittel und ihre verwendung als schaedlingsbekaempfungsmittel
FR2648140B1 (fr) 1989-06-08 1991-05-03 Centre Nat Rech Scient Procede de preparation d'oligomeres d'heterocycles aromatiques par couplage oxydant d'oligomeres inferieurs
DE3927786A1 (de) 1989-08-23 1991-02-28 Bayer Ag Verfahren zur herstellung von aldehyden
JPH03101679A (ja) 1989-09-14 1991-04-26 Sankyo Co Ltd リゾキシン誘導体
DK0431519T3 (da) 1989-12-04 1994-07-04 Searle & Co System til transdermal indgivelse af albuterol
EP0434517A3 (en) 1989-12-20 1991-10-16 Rhone-Poulenc Chimie Process for the preparation of mono- or poly-alkoxylated aromatic compounds
JPH03197441A (ja) 1989-12-26 1991-08-28 Sagami Chem Res Center カルボン酸類の製造方法
DE4005648A1 (de) 1990-02-22 1991-08-29 Wacker Chemie Gmbh Heteroarylenmethine und daraus hergestellte polymere
JP2916694B2 (ja) 1990-03-16 1999-07-05 コニカ株式会社 ハロゲン化銀写真感光材料及びその製造方法
JP2916700B2 (ja) 1990-07-05 1999-07-05 コニカ株式会社 ハロゲン化銀写真感光材料
EP0446899A1 (de) 1990-03-16 1991-09-18 Konica Corporation Photographisches Silberhalogenidmaterial
JPH0429969A (ja) 1990-05-28 1992-01-31 Nippon Oil & Fats Co Ltd ポリフルオロアルキル基含有ヘテロ芳香族誘導体及びその製造方法
US5034385A (en) 1990-06-26 1991-07-23 Merck & Co., Inc. 2-(heteroarylsubstituted)phenyl carbapenem antibacterial agents
IE74711B1 (en) 1990-07-27 1997-07-30 Ici Plc Fungicides
LU87821A1 (fr) 1990-10-12 1992-05-25 Cird Galderma Composes bi-aromatiques,et leur utilisation en medecine humaine et veterinaire et en cosmetique
DE4033563A1 (de) * 1990-10-22 1992-04-23 Henkel Kgaa Antiseborrhoische zubereitungen
US5354858A (en) 1991-03-28 1994-10-11 The University Of Toledo Production and use of Diels Alder adducts of vinyl porphyrins and of compositions containing such adducts
TW279162B (de) 1991-09-26 1996-06-21 Mitsubishi Chem Corp
US5352456A (en) 1991-10-10 1994-10-04 Cygnus Therapeutic Systems Device for administering drug transdermally which provides an initial pulse of drug
DE4138026A1 (de) 1991-11-19 1993-06-03 Bayer Ag Substituierte pyridin-4-carbonsaeureamide
DE69228827T2 (de) 1991-12-18 1999-10-21 Minnesota Mining And Mfg. Co., Saint Paul Mehrschichtige sperrstrukturen
FR2686162B1 (fr) 1992-01-13 1995-09-22 Commissariat Energie Atomique Modulateur spatial de lumiere a adressage optique.
EP0553769B1 (de) 1992-01-29 1996-01-03 FRANZ VÖLKL GmbH & CO. SKI UND TENNIS SPORTARTIKELFABRIK KG Ballspielschläger, insbesondere Tennisschläger
US5334389A (en) 1992-10-15 1994-08-02 Duke University Antifouling coating and method for using same
US6190894B1 (en) 1993-03-19 2001-02-20 The Regents Of The University Of California Method and compositions for disrupting the epithelial barrier function
US5998499A (en) 1994-03-25 1999-12-07 Dentsply G.M.B.H. Liquid crystalline (meth)acrylate compounds, composition and method
EP0640676B1 (de) 1993-08-31 1999-01-20 Canon Kabushiki Kaisha Mesomorphe Verbindung, eine diese enthaltene Flüssigkristallzusammensetzung, eine diese Zusammensetzung verwendende Flüssigkristallvorrichtung, Flüssigkristallapparat und Anzeigeverfahren
JP3015998B2 (ja) 1993-08-31 2000-03-06 キヤノン株式会社 液晶性化合物、それを含む液晶組成物、該液晶組成物を用いた液晶素子、液晶装置、並びに表示方法
US5569675A (en) 1994-03-07 1996-10-29 Bar Ilan University Methods of using carboxylic acid esters to increase fetal-hemoglobin levels
DE4412334A1 (de) 1994-04-11 1995-10-19 Hoechst Ag Substituierte N-Heteroaroylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament
FR2720393B1 (fr) 1994-05-27 1996-10-25 Rhone Poulenc Chimie Réactif utile pour et procédé pour la synthèse d'ester et xanthate transestérifiable.
DE4425146A1 (de) 1994-07-15 1996-01-18 Basf Ag Verwendung heterocyclischer Verbindungen
JPH0859611A (ja) 1994-08-26 1996-03-05 Nippon Soda Co Ltd ヘテロ環誘導体の製造法
US5512596A (en) 1994-09-02 1996-04-30 Gilead Sciences, Inc. Aromatic compounds
US5597826A (en) 1994-09-14 1997-01-28 Pfizer Inc. Compositions containing sertraline and a 5-HT1D receptor agonist or antagonist
TW307746B (de) 1994-10-14 1997-06-11 Sumitomo Chemical Co
US5702637A (en) 1995-04-19 1997-12-30 Minnesota Mining And Manufacturing Company Liquid crystal compounds having a chiral fluorinated terminal portion
CN1195352A (zh) 1995-07-27 1998-10-07 智索公司 有机硅组化合物,液晶组合物和液晶显示仪
US6756053B2 (en) 1995-07-28 2004-06-29 Zars, Inc. Controlled heat induced rapid delivery of pharmaceuticals from skin depot
US6013666A (en) 1996-07-02 2000-01-11 Sang Sup Jew Oxirane carboxylic acid derivative and its manufacturing method
GB9620061D0 (en) 1996-09-26 1996-11-13 Secr Defence Liquid crystalline (e,e)-butadiene compounds and mixtures and devices containing such compounds
WO1998017253A1 (en) 1996-10-23 1998-04-30 The Regents Of The University Of California Method and compositions for disrupting the epithelial barrier function
WO2000000204A1 (en) 1997-02-14 2000-01-06 Miravant Pharmaceuticals, Inc. Indium photosensitizers for pdt
US6541472B1 (en) 1997-02-21 2003-04-01 Viropharma Incorporated Compounds, compositions and methods for preventing and treating pestivirus infection and associated diseases
JPH10287654A (ja) 1997-04-11 1998-10-27 Nissan Chem Ind Ltd ピラゾロン誘導体及び除草剤
DE19717898A1 (de) 1997-04-28 1998-10-29 Agfa Gevaert Ag Farbfotografisches Aufzeichnungsmaterial
DE19718742A1 (de) 1997-05-02 1998-11-05 Hoechst Ag Verfahren zur Herstellung von aromatischen Aldehyden durch katalytische Gasphasenhydrierung der Carbonsäuren
ES2171022T3 (es) 1997-05-07 2002-08-16 Quadra Logic Tech Inc Esteres de etilenglicol de derivados de monohidrobenzoporfirinas como agentes fotoactivos.
JPH1143792A (ja) 1997-07-23 1999-02-16 Asahi Kagaku Kogyo Co Ltd 酸洗促進剤、酸洗促進剤を含んだ酸洗液組成物およびこれを用いる酸洗方法
US5851952A (en) 1997-11-07 1998-12-22 American Cyanamid Company Herbicidal thienyloxyazines
EP1028959B1 (de) 1997-11-07 2007-06-27 Basf Aktiengesellschaft Herbizide furanyl- und thienyloxyazine
US5869426A (en) 1997-11-07 1999-02-09 American Cyanamid Company Herbicidal 6-thienyloxypyrid-2-carboxamides
US6309561B1 (en) 1997-12-24 2001-10-30 3M Innovative Properties Company Liquid crystal compounds having a chiral fluorinated terminal portion
JP2002502852A (ja) 1998-02-09 2002-01-29 ３−ディメンショナル ファーマシューティカルズ， インコーポレイテッド プロテアーゼ阻害剤、特にウロキナーゼ阻害剤としてのヘテロアリールアミジン、メチルアミジンおよびグアニジン
WO1999048371A1 (en) 1998-03-27 1999-09-30 The Regents Of The University Of California Novel hiv integrase inhibitors and hiv therapy based on drug combinations including integrase inhibitors
JP4048645B2 (ja) 1998-04-10 2008-02-20 東レ株式会社 発光素子
US6232320B1 (en) 1998-06-04 2001-05-15 Abbott Laboratories Cell adhesion-inhibiting antiinflammatory compounds
SE9802793D0 (sv) 1998-08-21 1998-08-21 Astra Ab New compounds
US6139924A (en) 1998-11-20 2000-10-31 3M Innovative Properties Company Chiral liquid crystal compounds having a fluorinated terminal portion
AU2164300A (en) 1998-12-04 2000-06-26 N.V. Organon Substituted thiazoles for treatment of human diseases involving modulators of p-, l- and e- selectin
US6183773B1 (en) 1999-01-04 2001-02-06 The General Hospital Corporation Targeting of sebaceous follicles as a treatment of sebaceous gland disorders
DE19904389A1 (de) 1999-02-04 2000-08-10 Bayer Ag Verwendung von substituierten Isoxazolcarbonsäuren und Derivate und neue Stoffe
EA200100882A1 (ru) 1999-02-09 2002-04-25 3-Дименшенл Фамэсьютикэлс, Инк. Гетероарильные производные амидина, метиламидина и гуанидина (варианты), способ их получения, фармацевтическая композиция (варианты), способ ингибирования протеазы (варианты) и способ лечения различных заболеваний (варианты)
GB9906168D0 (en) 1999-03-17 1999-05-12 Rolic Ag Liquid crystal compounds
FR2793791B1 (fr) 1999-05-19 2002-01-25 Univ Paris 7 Denis Diderot Nouveaux composes inhibiteurs specifiques de phospholipases a2
CN1073571C (zh) 1999-06-02 2001-10-24 山西大学 单核芳香族、杂环类单酰异羟肟酸二烃基锡化合物及其合成
CN1367784A (zh) 1999-06-02 2002-09-04 盐野义制药株式会社 新的取代丙烯酮衍生物的制备方法
DE19929783A1 (de) 1999-06-29 2001-01-04 Bayer Ag Substituierte 6-[4-(Oxymethyl)-phenyl]-dihydropyridazinone und ihre Verwendung
JP2002060658A (ja) 2000-08-11 2002-02-26 Fuji Photo Film Co Ltd インクジェット用インク及びインクジェット記録方法
EP1578341A4 (de) 2000-10-11 2005-09-28 Tularik Inc Modulation der ccr4-funktion
US20050049242A1 (en) 2000-12-21 2005-03-03 W. Edward Robinson Novel HIV integrase inhibitors and HIV therapy based on drug combinations including integrase inhibitors
DE10104231A1 (de) 2001-01-31 2002-08-08 Consortium Elektrochem Ind Verfahren zur enzymatischen Herstellung von enantiomerenreinen 1,3-Dioxolan-4-on-Derivaten
US7709677B2 (en) 2001-01-31 2010-05-04 Glaxosmithkline Llc Process of preparing arylethanoldiamines
CA2439463A1 (en) 2001-02-28 2002-09-06 Anders Hallberg Diaminoquinazoline esters for use as dihydrofolate reductade inhibitors
US7534547B2 (en) 2001-03-29 2009-05-19 Osaka Gas Company Limited Optically active compound and photosensitive resin composition
JP2002363123A (ja) 2001-03-29 2002-12-18 Kansai Research Institute 光活性化合物および感光性樹脂組成物
ATE427948T1 (de) 2001-04-24 2009-04-15 Purdue Research Foundation Folat-mimetika und deren folatrezeptorbindende konjugate
DE10125145A1 (de) 2001-05-22 2002-11-28 Gruenenthal Gmbh Substituierte C-Furan-2-yl-methylamin- und C-Thiophen-2-yl-methylamin-Derivate
EP1270535A3 (de) 2001-06-20 2004-02-18 Clariant GmbH Verfahren zur Herstellung von substituierten aromatischen Verbindungen
EP1275301A1 (de) 2001-07-10 2003-01-15 Bayer CropScience S.A. Trisubstituierte heterocyclische Verbindungen und ihre Verwendung als Fungizide
JP2003055367A (ja) 2001-08-15 2003-02-26 Kuraray Co Ltd ３−ホルミルフラン類の製造方法
JP2005194190A (ja) 2001-10-05 2005-07-21 Fumie Satou １９−ノル−ビタミンｄ誘導体の製造法
FR2831537B1 (fr) 2001-10-26 2008-02-29 Aventis Pharma Sa Nouveaux derives de benzimidazoles, leur procede de preparation, leur application a titre de medicament, compositions pharmaceutiques et nouvelle utilisation
US6897208B2 (en) 2001-10-26 2005-05-24 Aventis Pharmaceuticals Inc. Benzimidazoles
AU2002334217B2 (en) 2001-10-26 2008-07-03 Aventis Pharmaceuticals Inc. Benzimidazoles and analogues and their use as protein kinases inhibitors
AUPR970701A0 (en) 2001-12-21 2002-01-24 Fujisawa Pharmaceutical Co., Ltd. Benzhydryl derivatives
US7160921B2 (en) 2002-01-29 2007-01-09 The Gillette Company Reduction of hair growth
JP4157765B2 (ja) 2002-02-18 2008-10-01 花王株式会社 粉末油脂
US7122296B2 (en) 2002-03-05 2006-10-17 Brewer Science Inc. Lithography pattern shrink process and articles
AU2003251942A1 (en) 2002-07-17 2004-02-02 Titan Pharmaceuticals, Inc. Combination of chemotherapeutic drugs for increasing antitumor activity
JP2004107271A (ja) 2002-07-22 2004-04-08 Mitsubishi Rayon Co Ltd 水溶性アルキルホスフィン誘導体とその製造方法、ホスフィン配位子錯体並びにビアリール誘導体の製造方法
JP4468810B2 (ja) 2002-07-24 2010-05-26 キューエルティー インコーポレーティッド ピラゾリルベンゾチアゾール誘導体および治療薬としてのそれらの使用法
DE10240261A1 (de) 2002-08-31 2004-03-11 Clariant Gmbh Verfahren zur metallorganischen Herstellung organischer Zwischenprodukte über Halogen-Metall-Austauschreaktionen
DE10240262A1 (de) 2002-08-31 2004-03-11 Clariant Gmbh Verfahren zur metallorganischen Herstellung organischer Zwischenprodukte über Aryllithium-Basen
MXPA05004811A (es) 2002-11-06 2005-07-22 Schering Corp Inhibidores de absorcion de colesterol para el tratamiento de trastornos autoinmunes.
TW585898B (en) 2002-12-26 2004-05-01 Ind Tech Res Inst Liquid crystal compounds with optical activities having high helical twisting power, method for preparing the same, and liquid crystal composition containing the compounds
EP2404676A1 (de) 2002-12-30 2012-01-11 The Regents of the University of California Mikrofluidische Steuerungsstrukturen
DE10300097A1 (de) 2003-01-07 2004-07-22 Bayer Ag Kupfer-Komplexe und ihre Verwendung
JP4083028B2 (ja) 2003-02-04 2008-04-30 広栄化学工業株式会社 アリールボラン化合物の製造方法
DE602004024375D1 (de) 2003-02-14 2010-01-14 Glaxo Group Ltd Carboxamidderivate
US7029729B2 (en) 2003-02-24 2006-04-18 3M Innovative Properties Company Cholesteric liquid crystal additives
CN100402503C (zh) 2003-03-28 2008-07-16 日产化学工业株式会社 丙烯腈化合物的制造方法
JP4715992B2 (ja) 2003-03-28 2011-07-06 日産化学工業株式会社 アクリロニトリル化合物の製造方法
WO2004111199A2 (en) 2003-06-12 2004-12-23 University Of Colorado System Technology Systems and methods for treating human inflammatory and proliferative diseases and wounds, with fatty acid metabolism inhibitors and/or glycolytic inhibitors
WO2004113258A1 (ja) 2003-06-20 2004-12-29 Shionogi & Co., Ltd. 炭素−炭素結合生成反応
ITMI20031941A1 (it) * 2003-10-09 2005-04-10 Sinclair Pharmaceuticals Ltd Composizioni farmaceutiche topiche per il trattamento delle dermatiti
US20050250794A1 (en) 2003-12-19 2005-11-10 Andrew Napper Methods of treating a disorder
US8119684B2 (en) 2003-12-30 2012-02-21 Dana-Farber Cancer Institute, Inc. Thiophene derivatives for up-regulating HLA-DM activity
US7510710B2 (en) 2004-01-08 2009-03-31 The Regents Of The University Of Colorado Compositions of UCP inhibitors, Fas antibody, a fatty acid metabolism inhibitor and/or a glucose metabolism inhibitor
JP2007529422A (ja) 2004-01-29 2007-10-25 エリクシアー ファーマシューティカルズ， インコーポレイテッド 抗ウイルス治療
US7297168B2 (en) 2004-02-02 2007-11-20 The Procter & Gamble Company Keratin dyeing compounds, keratin dyeing compositions containing them, and use thereof
CA2457214A1 (en) 2004-02-06 2005-08-06 Qlt Inc. Photodynamic therapy for the treatment of acne
JP2007534735A (ja) 2004-04-28 2007-11-29 アロウ セラピューティクス リミテッド 抗ウイルス剤として使用するためのモルホリニルアニリノキナゾリン誘導体
US7534505B2 (en) 2004-05-18 2009-05-19 The University Of Southern California Organometallic compounds for use in electroluminescent devices
US7279704B2 (en) 2004-05-18 2007-10-09 The University Of Southern California Complexes with tridentate ligands
US7445855B2 (en) 2004-05-18 2008-11-04 The University Of Southern California Cationic metal-carbene complexes
US7154114B2 (en) 2004-05-18 2006-12-26 Universal Display Corporation Cyclometallated iridium carbene complexes for use as hosts
US7491823B2 (en) 2004-05-18 2009-02-17 The University Of Southern California Luminescent compounds with carbene ligands
US7601436B2 (en) 2004-05-18 2009-10-13 The University Of Southern California Carbene metal complexes as OLED materials
US7582365B2 (en) 2005-01-10 2009-09-01 Universal Display Corporation Reversibly reducible metal complexes as electron transporting materials for OLEDs
WO2005113704A2 (en) 2004-05-18 2005-12-01 The University Of Southern California Luminescent compounds with carbene ligands
US7393599B2 (en) 2004-05-18 2008-07-01 The University Of Southern California Luminescent compounds with carbene ligands
US7655323B2 (en) 2004-05-18 2010-02-02 The University Of Southern California OLEDs utilizing macrocyclic ligand systems
US7598388B2 (en) 2004-05-18 2009-10-06 The University Of Southern California Carbene containing metal complexes as OLEDs
JP2005350527A (ja) 2004-06-09 2005-12-22 Kyowa Hakko Chemical Co Ltd 環状保護基で置換された単量体および重合体
WO2005123667A1 (en) 2004-06-22 2005-12-29 Syngenta Participations Ag Substituted bicyclooctenes and their use as herbicides
US7790935B2 (en) 2004-08-23 2010-09-07 Sun Pharma Global Fze Process for preparation of citalopram and enantiomers
MX2007004036A (es) 2004-10-08 2007-05-24 Unilever Nv Complejo de hierro para uso en el tratamiento y/o prevencion de trastornos nutricionales.
KR100784337B1 (ko) 2004-11-12 2007-12-13 한국생명공학연구원 신규한 ｏ-아실옥심 유도체, 그의 제조방법 및 이를유효성분으로 하는 심장순환계 질환의 예방 및 치료용약학 조성물
US6987207B1 (en) 2005-03-03 2006-01-17 Alan Jeffrey Ronyak Hydrocarbonaceous composition
CA2603534C (en) 2005-03-04 2014-02-04 Fan Wu Design and synthesis of novel antimicrobials
GB0505861D0 (en) 2005-03-22 2005-04-27 Univ Cardiff Methods for the synthesis of heteroaromatic compounds
ME02051B (me) 2005-04-13 2015-05-20 Astex Therapeutics Ltd Derivati hidroksibenzamida i njihova primena kao inhibitora hsp90
EP1889049A2 (de) 2005-05-25 2008-02-20 The Board of Governors for Higher Education State of Rhode Island And Providence Plantations Thermochrome und thermofluoreszierende pigmente: intensivierung von farbe und fluoreszenz mit zusätzen
WO2007019295A1 (en) 2005-08-05 2007-02-15 Cylene Pharmaceuticals, Inc. Methods of preparing quinolone analogs
DE102005045132A1 (de) 2005-09-22 2007-03-29 Archimica Gmbh Verfahren zur Herstellung von 2-Arylcarbonylverbindungen, 2-Arylestern und 2-Arylnitrilen sowie ihrer heteroaromatischen Analoga
EP1787981A1 (de) 2005-11-22 2007-05-23 Bayer CropScience S.A. Neue N-phenethylcarboxamidderivate
WO2007064861A2 (en) 2005-12-02 2007-06-07 Brandeis University Asymmetric friedel-crafts alkylations catalyzed by byfunctional cinchona alkaloids
US20070203236A1 (en) 2006-01-11 2007-08-30 Smith Jeffrey W Novel antagonists of the human fatty acid synthase thioesterase
JP4895267B2 (ja) 2006-02-21 2012-03-14 三菱レイヨン株式会社 ３，６−エポキシ−１，２，３，６−テトラヒドロフタル酸無水物誘導体の製造方法
DE602006007804D1 (de) 2006-03-31 2009-08-27 Sony Deutschland Gmbh Zusammensetzung die mindestens eine Art von Flüssigkristall enthält
EP1840188B1 (de) 2006-03-31 2011-09-07 Sony Deutschland GmbH Zusammensetzung mit mindestens einer Art von Flüssigkristall
US20080027044A1 (en) 2006-06-13 2008-01-31 Kim Lewis Prodrug antibiotic screens
WO2008003746A1 (en) 2006-07-06 2008-01-10 Bayer Cropscience Sa N-(4-pyridin-2-ylbutyl) carboxamide derivatives, their process of preparation and their use as fungicides
EP2054058B1 (de) 2006-08-04 2016-11-09 Beth Israel Deaconess Medical Center Pyruvatkinasehemmer und verfahren zur behandlung von erkrankungen
DE102006037399A1 (de) 2006-08-10 2008-02-14 Archimica Gmbh Verfahren zur Herstellung von Arylaminen
US7858126B2 (en) 2006-08-31 2010-12-28 Trinity Laboratories Inc. Derivatives of sandalwood oil and santalols for treating cold sores and herpes
US20080161324A1 (en) 2006-09-14 2008-07-03 Johansen Lisa M Compositions and methods for treatment of viral diseases
US20100204317A1 (en) 2006-11-03 2010-08-12 Qlt Inc. Methods of treating dermatological disorders or conditions
RU2319694C1 (ru) 2007-01-19 2008-03-20 Михаил Иванович Власов Способ получения производных 3-гидроксипиридина
CL2008000512A1 (es) 2007-02-22 2008-08-29 Bayer Cropscience Sa Compuestos derivados de n-(3-fenilpropil)carboxamida; procedimiento de preparacion de dichos compuestos; composicion fungicida; y metodo para combatir de forma preventiva o curativa los hongos fitopatogenos de cultivos.
WO2008131258A2 (en) 2007-04-19 2008-10-30 State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of Oregon State University Pactamycin biosynthetic gene cluster
CN101820757A (zh) * 2007-06-01 2010-09-01 普林斯顿大学托管委员会 通过调节宿主细胞代谢途径治疗病毒感染
HUP0700395A2 (en) 2007-06-07 2009-03-02 Sanofi Aventis Substituted [1,2,4] triazolo [1,5-a] quinolines, process for their preparation, pharmaceutical compositions thereof, and intermediates
EP2167074A2 (de) 2007-06-13 2010-03-31 NorthEastern University Antibiotische verbindungen
EP2003125A1 (de) 2007-06-14 2008-12-17 Total Petrochemicals Research Feluy Neue Tridentat-Ligandverbindungen mit Iminofuraneinheiten, Verfahren zur Herstellung dieser Verbindungen und ihre Verwendung bei der Herstellung von Katalysatoren zur Homopolymerisation und Copolymerisation von Ethylen und Alpha-Olefinen
GB0715454D0 (en) 2007-08-08 2007-09-19 Syngenta Ltd Novel herbicides
GB0715576D0 (en) 2007-08-09 2007-09-19 Syngenta Ltd Novel herbicides
JP5365806B2 (ja) 2007-09-10 2013-12-11 日産化学工業株式会社 置換イソキサゾリン化合物及び有害生物防除剤
BRPI0817897A2 (pt) 2007-11-02 2019-09-24 Methylgene Inc composto, composição, e, métodos de inibição da atividade hdac, e de tratamento de uma doença responsiva a um inibidor de atividade hdac
JP5583592B2 (ja) 2007-11-30 2014-09-03 ニューリンク ジェネティクス コーポレイション Ｉｄｏ阻害剤
AU2009243756B2 (en) 2008-05-05 2013-06-27 Sanofi-Aventis Acylamino-substituted fused cyclopentanecarboxylic acid derivatives and their use as pharmaceuticals
JP2010235590A (ja) 2009-03-09 2010-10-21 Nissan Chem Ind Ltd 置換イソキサゾリン化合物及び有害生物防除剤
CN101857622B (zh) 2009-04-07 2014-12-03 中国医学科学院药物研究所 一种腺苷衍生物及其制备方法和应用
US8884034B2 (en) 2009-07-08 2014-11-11 Dermira (Canada), Inc. TOFA analogs useful in treating dermatological disorders or conditions
CN101704700B (zh) 2009-10-28 2012-04-11 东北师范大学 一种氢溴酸(溴化氢)催化芳烃的傅-克反应方法
AR079022A1 (es) 2009-11-02 2011-12-21 Sanofi Aventis Derivados de acido carboxilico ciclico sustituidos con acilamino, su uso como productos farmaceuticos, composicion farmaceutica y metodo de preparacion
US8920681B2 (en) 2009-12-30 2014-12-30 Korea University Research And Business Foundation Electrically conductive polymers with enhanced conductivity
TWI532725B (zh) 2010-01-26 2016-05-11 賽諾菲阿凡提斯公司 經氧取代之３－雜芳醯基胺基－丙酸衍生物及其作為藥物之用途
CN102134180A (zh) 2011-01-06 2011-07-27 华东理工大学 一种呋喃衍生物的开环加氢反应新方法
AU2012205410A1 (en) 2011-01-13 2013-08-01 Qlt Inc. Pharmaceutical compositions for topical delivery of photosensitizers and uses thereof

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HK1189886A1 (en) 2014-06-20
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CN102482249A (zh) 2012-05-30
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